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An orally delivered small-molecule formulation with antiangiogenic and anticancer activity

Abstract

Targeting angiogenesis, the formation of blood vessels, is an important modality for cancer therapy. TNP-470, a fumagillin analog, is among the most potent and broad-spectrum angiogenesis inhibitors. However, a major clinical limitation is its poor oral availability and short half-life, necessitating frequent, continuous parenteral administration. We have addressed these issues and report an oral formulation of TNP-470, named Lodamin. TNP-470 was conjugated to monomethoxy-polyethylene glycol–polylactic acid to form nanopolymeric micelles. This conjugate can be absorbed by the intestine and selectively accumulates in tumors. Lodamin significantly inhibits tumor growth, without causing neurological impairment in tumor-bearing mice. Using the oral route of administration, it first reaches the liver, making it especially efficient in preventing the development of liver metastasis in mice. We show that Lodamin is an oral nontoxic antiangiogenic drug that can be chronically administered for cancer therapy or metastasis prevention.

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Figure 1: Lodamin synthesis and characterization.
Figure 2: Effect of Lodamin on angiogenesis and cell uptake of the drug.
Figure 3: Intestinal absorption and body distribution studies.
Figure 4: Lodamin inhibits primary tumor growth without causing neurotoxicity.
Figure 5: Lodamin effect on tumor structure, cell proliferation, angiogenesis and apoptosis.
Figure 6: Lodamin inhibits liver metastasis in mice injected with B16/F10 cells into their spleen.

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References

  1. Holmgren, L., O'Reilly, M. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat. Med. 1, 149–153 (1995).

    Article  CAS  Google Scholar 

  2. Naumov, G. & Folkman, J. Strategies to prolong the nonangiogenic dormant state of human cancer. in Antiangiogenic cancer therapy Edn. 1. (ed. Darren, W., Herbst, R.S., Abbruzzese, J.L.) 3–23 (CRS Press, Boca Raton, FL, Taylor and Francis, 2007).

    Google Scholar 

  3. Ingber, D. et al. Synthetic analogue of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348, 555–557 (1990).

    Article  CAS  Google Scholar 

  4. Folkman, J. & Kalluri, R. Tumor angiogenesis. in Cancer Medicine Vol. 1. (ed. Kufe, D. et al.) 161–194 (B.C. Decker Inc., Hamilton, Ontario, 2003).

    Google Scholar 

  5. Yamaoka, M., Yamamoto, T., Ikeyama, S., Sudo, K. & Fujita, T. Angiogenesis inhibitor TNP-470 (AGM-1470) potently inhibits the tumor growth of hormone-independent human breast and prostate carcinoma cell lines. Cancer Res. 53, 5233–5236 (1993).

    CAS  PubMed  Google Scholar 

  6. Shusterman, S. et al. The angiogenesis inhibitor tnp-470 effectively inhibits human neuroblastoma xenograft growth, especially in the setting of subclinical disease. Clin. Cancer Res. 7, 977–984 (2001).

    CAS  PubMed  Google Scholar 

  7. Yanase, T., Tamura, M., Fujita, K., Kodama, S. & Tanaka, K. Inhibitory effect of angiogenesis inhibitor TNP-470 on tumor growth and metastasis of human cell lines in vitro and in vivo. Cancer Res. 53, 2566–2570 (1993).

    CAS  PubMed  Google Scholar 

  8. Takamiya, Y., Brem, H., Ojeifo, J., Mineta, T. & Martuza, R. AGM-1470 inhibits the growth of human glioblastoma cells in vitro and in vivo. Neurosurgery 34, 869–875 (1994).

    CAS  PubMed  Google Scholar 

  9. Takamiya, Y., Friedlander, R.M., Brem, H. & Malick, A. Martuza, RL Inhibition of angiogenesis and growth of human nerve-sheath tumors by AGM-1470. J. Neurosurg. 78, 470–476 (1993).

    Article  CAS  Google Scholar 

  10. Emoto, M., Tachibana, K., Iwasaki, H. & Kawarabayashi, T. Antitumor effect of TNP-470, an angiogenesis inhibitor, combined with ultrasound irradiation for human uterine sarcoma xenografts evaluated using contrast color Doppler ultrasound. Cancer Sci. 98, 929–935 (2007).

    Article  CAS  Google Scholar 

  11. Nahari, D. et al. Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer. Mol. Cancer Ther. 6, 1329–1337 (2007).

    Article  CAS  Google Scholar 

  12. Kanamori, M., Yasuda, T., Ohmori, K., Nogami, S. & Aoki, M. Genetic analysis of high-metastatic clone of RCT sarcoma in mice, and its growth regression in vivo in response to angiogenesis inhibitor TNP-470. J. Exp. Clin. Cancer Res. 26, 101–107 (2007).

    CAS  PubMed  Google Scholar 

  13. Sin, N. et al. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc. Natl. Acad. Sci. USA 94, 6099–6103 (1997).

    Article  CAS  Google Scholar 

  14. Zhang, Y., Griffith, E., Sage, J., Jacks, T. & Liu, J. Cell cycle inhibition by the anti-angiogenic agent TNP-470 is mediated by p53 and p21WAF1/CIP1. Proc. Natl. Acad. Sci. USA 97, 6427–6432 (2000).

    Article  CAS  Google Scholar 

  15. Mauriz, J. et al. Cell-cycle inhibition by TNP-470 in an in vivo model of hepatocarcinoma is mediated by a p53 and p21WAF1/CIP1 mechanism. Transl. Res. 149, 46–53 (2007).

    Article  CAS  Google Scholar 

  16. Kruger, E. & Figg, W.D. TNP-470: an angiogenesis inhibitor in clinical development for cancer. Expert Opin. Investig. Drugs 9, 1383–1396 (2000).

    Article  CAS  Google Scholar 

  17. Kudelka, A., Verschraegen, C. & Loyer, E. Complete remission of metastatic cervical cancer with the angiogenesis inhibitor TNP-470. N. Engl. J. Med. 338, 991–992 (1998).

    Article  CAS  Google Scholar 

  18. Tran, H. et al. Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in combination with paclitaxel and carboplatin in patients with solid tumors. Cancer Chemother. Pharmacol. 54, 308–314 (2004).

    Article  CAS  Google Scholar 

  19. Kudelka, A. et al. A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix. Clin. Cancer Res. 3, 1501–1505 (1997).

    CAS  PubMed  Google Scholar 

  20. Herbst, R. et al. Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer. J. Clin. Oncol. 20, 4440–4447 (2002).

    Article  CAS  Google Scholar 

  21. Stadler, W. et al. Multi-institutional study of the angiogenesis inhibitor TNP-470 in metastatic renal carcinoma. J. Clin. Oncol. 17, 2541–2545 (1999).

    Article  CAS  Google Scholar 

  22. Logothetis, C. et al. Phase I trial of the angiogenesis inhibitor TNP-470 for progressive androgen-independent prostate cancer. Clin. Cancer Res. 7, 1198–1203 (2001).

    CAS  PubMed  Google Scholar 

  23. Bhargava, P. et al. A phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer. Clin. Cancer Res. 5, 1989–1995 (1999).

    CAS  Google Scholar 

  24. Satchi-Fainaro, R. et al. Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat. Med. 10, 255–261 (2004).

    Article  CAS  Google Scholar 

  25. Cretton-Scott, E., Placidi, L., McClure, H., Anderson, D. & Sommadossi, J. Pharmacokinetics and metabolism of O-(chloroacetyl-carbamoyl) fumagillol (TNP-470, AGM-1470) in rhesus monkeys. Cancer Chemother. Pharmacol. 38, 117–122 (1996).

    Article  Google Scholar 

  26. Kataoka, K., Harada, A. & Nagasaki, Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv. Drug Deliv. Rev. 47, 113–131 (2001).

    Article  CAS  Google Scholar 

  27. Harris, J. & Chess, R. Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov. 2, 214–221 (2003).

    Article  CAS  Google Scholar 

  28. Edlund, U. & Albertsson, A. Degradable polymer microspheres for controlled drug delivery. Adv. Polym. Sci. 157, 67–112 (2001).

    Article  Google Scholar 

  29. Rogers, M., Birsner, A. & D'Amato, R. The mouse cornea micropocket angiogenesis assay. Nat. Protoc. 2, 2545–2550 (2007).

    Article  CAS  Google Scholar 

  30. Carter, R., Morton, A. & Dunnett, S. Motor coordination and balance in rodents. in Current Protocols in Neuroscience Vol. 8.12. (ed. Taylor G.), 1–8 (John Wiley & Sons, Inc, New York, 2001).

    Google Scholar 

  31. Almog, N. et al. Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis. FASEB J. 20, 947–949 (2006).

    Article  CAS  Google Scholar 

  32. Marler, J. et al. Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies. Pediatrics 116, 38–45 (2005).

    Article  Google Scholar 

  33. Folkman, J. & Klement, G. Platelet biomarkers for the detection of disease. US and International Patent 20060204951 (2006).

  34. Cervi, D. et al. Platelet-associated PF-4 as a biomarker of early tumor growth. Blood (2007).

  35. Kwon, Y. Handbook of Essential Pharmacokinetics, Pharmacodynamics and Drug Metabolism for Industrial Scientists. (Plenum, New York, 2001).

    Google Scholar 

  36. Pierri, E. & Avgoustakis, K. Poly(lactide)-poly(ethylene glycol) micelles as a carrier for griseofulvin. J. Biomed. Mater. Res. A 75, 639–647 (2005).

    Article  CAS  Google Scholar 

  37. Kakizawa, Y. & Kataoka, K. Block copolymer micelles for delivery of gene and related compounds. Adv. Drug Deliv. Rev. 54, 203–222 (2002).

    Article  CAS  Google Scholar 

  38. Torchilin, V. Targeted polymeric micelles for delivery of poorly soluble drugs. Cell. Mol. Life Sci. 61, 2549–2559 (2004).

    Article  CAS  Google Scholar 

  39. Nishiyama, N. & Kataoka, K. Current state, achievements, and future prospects of polymeric micelles as nanocarriers for drug and gene delivery. Pharmacol. Ther. 112, 630–648 (2006).

    Article  CAS  Google Scholar 

  40. Barbera-Guillem, E., Smith, I. & Weiss, L. Cancer-cell traffic in the liver. I. Growth kinetics of cancer cells after portal-vein delivery. Int. J. Cancer 52, 974–977 (1992).

    Article  CAS  Google Scholar 

  41. Greish, K. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J. Drug Target. 15, 457–464 (2007).

    Article  CAS  Google Scholar 

  42. Duncan, R. Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer 6, 688–701 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Donald Ingber for his support and encouragement of this work, Daniela Prox and Jenny Mu for their assistance with animal studies and chemical analysis, Kristin Johnson for the graphic work, Chun Wang (University of Minnesota) for fruitful discussions. We thank D. Figg, National Cancer Institute, for TNP-470. This work is supported in part by a Department of Defense Congressional Award W81XWH-05-1-0115 (to J.F.). The submission of this paper was completed before Folkman passed away in January and is dedicated to him for his support and mentorship.

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Authors

Contributions

O.B. designed and developed Lodamin formulation, designed experiments, performed tissue culture, in vivo studies and histology, analyzed data and wrote the manuscript; O.F. conducted intrasplenic injections, assisted with editing the manuscript; A.A. and I.A. assisted with cell assays and histology; F.C. conducted TEM imaging and analysis; L.B. assisted with animal studies and conducted corneal assays; E.P. performed confocal microscope imaging; Y.N. performed liver toxicity assays; S.K. and G.C. designed, conducted and analyzed neurotoxicity tests in mice; R.J.D. advised, edited the revisited manuscript and supervised corneal assays. J.F. supervised the entire study, designed experiments, analyzed data and edited the manuscript.

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Correspondence to Ofra Benny.

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Competing interests

We have filed a patent (on June, 2007, Benny, O., Folkman, J., “Fumagillol derivative polymersomes for oral administration,” Children’s Hospital Boston (CHB)). As per CHB policy, the patent application has been assigned to CHB, and CHB is responsible for the optioning and licensing of the patent application. Lodamin is under option for licensing to a company for development as a pharmaceutical drug.

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Benny, O., Fainaru, O., Adini, A. et al. An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nat Biotechnol 26, 799–807 (2008). https://doi.org/10.1038/nbt1415

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